Abstract
Exome sequencing is utilized in routine clinical genetic diagnosis. The technical robustness of repurposing large-scale next-generation sequencing data for pharmacogenetics has been demonstrated, supporting the implementation of preemptive pharmacogenetic strategies based on adding clinical pharmacogenetic interpretation to exomes. However, a comprehensive study analyzing all actionable pharmacogenetic alleles contained in international guidelines and applied to diagnostic exome data has not been performed. Here, we carried out a systematic analysis based on 5001 Spanish or Latin American individuals with diagnostic exome data, either Whole Exome Sequencing (80%), or the so-called Clinical Exome Sequencing (20%) (60 Mb and 17 Mb, respectively), to provide with global and gene-specific clinical pharmacogenetic utility data. 788 pharmacogenetic alleles, distributed through 19 genes included in Clinical Pharmacogenetics Implementation Consortium guidelines were analyzed. We established that Whole Exome and Clinical Exome Sequencing performed similarly, and 280 alleles in 11 genes (CACNA1S, CYP2B6, CYP2C9, CYP4F2, DPYD, G6PD, NUDT15, RYR1, SLCO1B1, TPMT, and UGT1A1) could be used to inform of pharmacogenetic phenotypes that change drug prescription. Each individual carried in average 2.2 alleles and overall 95% (n = 4646) of the cohort could be informed of at least one actionable pharmacogenetic phenotype. Differences in variant allele frequency were observed among the populations studied and the corresponding gnomAD population for 7.9% of the variants. In addition, in the 11 selected genes we uncovered 197 novel variants, among which 27 were loss-of-function. In conclusion, we provide with the landscape of actionable pharmacogenetic information contained in diagnostic exomes, that can be used preemptively in the clinics.
Highlights
Adverse Reactions to Drugs (ADRs) and therapeutic failure are major public health care problems[1,2]
Exome sequencing is limited by design, but at the moment, the large-scale next-generation sequencing (NGS) techniques most commonly used for diagnosis are Whole exome sequencing (WES) together with the so-called Clinical Exome Sequencing (CES), which are smaller designs targeting disease-causing genes[27–29]
whole-genome sequencing (WGS) is taking the lead for genomics medicine[37], but WES and CES provide with an invaluable resource[38–40] and a unique opportunity to implement pharmacogenetics, since they represent a competitive option among the large-scale NGS techniques used in the clinic[41,42]
Summary
Adverse Reactions to Drugs (ADRs) and therapeutic failure are major public health care problems[1,2]. All pharmacogenetic alleles described in any of the 25 that contributed the most to the total alleles called, followed by available CPIC clinical guidelines (https://cpicpgx.org/guidelines/; CYP4F2, CYP2C9, and SLCO1B1, while a low number of alleles were accessed in July 2021) were selected for the study (788 alleles distributed in 19 genes) We filtered out those with no application in the clinics (with normal function, with unclear/uncertain/ unknown impact in function or with a limited/inadequate strength of evidence, when available; 345 alleles discarded and 443 retained), we identified alleles defined by intronic, intergenic or upstream regions variants not present in the exome data (5001 exomes analyzed; 33 alleles discarded and 410 retained). In CES there was a lower 0.003 versus 0.00078 for Latin American countries and gnomAD coverage in CACNA1S caused by the variant rs772226819 (40% of AMR) suggesting a contribution from Sub-Saharan Africa in our npj Genomic Medicine (2022) 12
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